Systemic sclerosis (SSc; Scleroderma) is a connective tissue disease of unknown etiology that is associated with significant morbidity and mortality. It has long been presumed that SSc likely results from environmental triggers, although these environmental insults have not been identified. The gold standard for assessing the role of environmental and inherited genetic effects on the development of a disease is the study of twins. A cross sectional study of twins with SSc we conducted several years ago showed a comparable concordance for disease of approximately 5% in monozygotic (MZ) and dizygotic (DZ) twins. Published research on familial cases of SSc, in conjunction with findings from our twin study, suggests that SSc likely develops in individuals with a genetically susceptible background upon exposure to appropriate environmental triggers or via acquired genetic changes. We therefore propose in specific aim 1 to identify environmental factors that may associate with SSc using the twin cohort and a large cohort of SSc patients and matched controls. Since epigenetic regulation has emerged as an important mechanism mediating gene expression and the manifestation of a disease phenotype, specific aim 2 is designed to compare the DNA methylation profile of twins participating in our study. Lastly, we will explore the effect of environmental factors on DNA methylation in specific aim 3. Our findings will significantly advance our understanding of disease pathogenesis in SSc, provide novel insights into epigenetic mechanisms underlying the disease, and identify a causal relationship between environmental factors and altered DNA methylation. Our findings will propel progress in the field and provide new avenues for research for mentees to facilitate their research and allow them to establish their own independent research programs. These mentees will be integral participants in the PI's program throughout the award period. The PI will mentor young physician scientists in the assessment of SSc in patients and the absence of disease in healthy twins, the evaluation of Raynaud phenomenon, obtaining informed consent, administration of questionnaire to patients and controls, use of clinical samples, the examination of DNA methylation profiles, the application of the University of Pittsburgh Scleroderma SerumBank and matching clinical Database to their research projects, and the analysis of environmental factors on DNA methylation. Together, these approaches will train the mentees in epidemiology, identification of risk factors, environmental medicine, and clinical epigenetics. The mentoring goals of this application also include mentoring young physician scientists in patient-oriented research, grantsmanship, manuscript writing, responsible conduct of research, and career development. The PI's reputation as an excellent mentor coupled with the collaborative and supportive environment at the University of Pittsburgh, the resources available at the institution and via the CTSI, and the resources of the Scleroderma Center of Pittsburgh, provide the perfect environment for attracting and training successful physician scientists. Our success will provide a pipeline of clinical investigators to continue the mission of treating patients and identifying te cause and cure for Scleroderma and related diseases.